Transmission Reduction and Prevention With HPV Vaccination (TRAP-HPV) Study: A Randomized Controlled Trial of the Efficacy of HPV Vaccination in Preventing Transmission of HPV Infection in Heterosexual Couples
Two prophylactic vaccines (Gardasil by Merck, and Cervarix by GlaxoSmithKline) have been
proven in randomized controlled trials (RCT) to be highly effective in preventing infection
against the target HPV types (HPV-6/11/16/18, for Gardasil, and HPV-16/18, for Cervarix) and
the cervical precancerous lesions caused by them. These vaccines have shifted the paradigm
of prevention and are expected to have a major impact in reducing the burden of cervical
cancer and of other HPV-associated malignancies, such as vulvar, vaginal, penile, anal, and
oropharyngeal cancers, as well as benign HPV-associated conditions (in the case of
Gardasil), such as anogenital warts and respiratory papillomatosis. However, little is known
about the extent with which vaccination may reduce transmission between sexual partners;
i.e. much remains to be understood on the effects of HPV vaccine in preventing transmission
of target HPV types to sexual partners of vaccinated individuals and its impact on herd
The investigators propose to conduct a placebo-controlled, double-blinded RCT to measure the
impact of vaccination in preventing HPV transmission within young (age 18-26) heterosexual
couples at McGill and Concordia Universities in Montreal, Canada. Individual partners in 500
couples will be randomized to a treatment (Gardasil) or a control vaccine (Havrix, a
hepatitis A vaccine). This control vaccine provides a similar health benefit incentive as
HPV vaccination while preserving the scientific cogency of a "placebo" comparator. Risk
factor data will be collected via computerized questionnaires at enrolment (time 0), 2, 4,
6, 9 and 12 months. At all time points, the investigators will measure HPV DNA infection
status by PCR in both partners in exfoliated penile, anal, and oral samples from men and
vaginal, anal, oral samples from women. Assessing pre-enrolment humoral immune response to
HPV infection with a competitive Luminex immunoassay (CLIA) will be done in an enrolment
blood sample from all study participants.
The primary outcome will be the reduction of HPV DNA positivity for the target HPV vaccine
types (types 6, 11, 16, and 18) in multiple anatomic sites in Havrix-treated sexual partners
of participants who received Gardasil. The investigators hypothesize that HPV vaccination is
effective in reducing the risk of HPV transmission to their sexual partners. They will use
the Kaplan-Meier technique and logrank tests to compare the cumulative probability of HPV
infection in sexual partners of vaccinated versus unvaccinated individuals against follow-up
time, and Cox proportional hazards regression to estimate the effect of vaccination and
other covariates on transmission of HPV to sexual partners. Statistical analyses will follow
an intention-to-treat approach but additional regression models will examine the role of
several candidate determinants in mediating transmission and the protective effects.
Mixed-effects models will also be used to take advantage of the repeated measurements across
visits, HPV types, and anatomical sites for the same subject.
In addition to the findings on protection to unvaccinated partners, it is expected that this
study will provide valuable insights as to whether protection may exist for a vaccine
recipient in preventing infection in an anatomical site in which a target type has not yet
established infection. These findings will generate key parameter data to inform the extent
of herd immunity in cost-effectiveness models of HPV vaccination. Such models are essential
to arrive at rational science-driven policies of HPV vaccination in girls and boys in
(full protocol available upon request)
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
The primary outcome will be the reduction of HPV DNA positivity for the target HPV vaccine types (i.e., HPVs 6, 11, 16, and 18) in multiple anatomic sites in the placebo-treated sexual partners of persons who received Gardasil.
Reduction in HPV type concordance (for the four target types) will be the main outcome evaluable as per the above group contrasts. These comparisons will be done with due attention to the enrolment virological status of the individuals. For instance, it is expected that a Havrix-treated woman who is positive for HPV 6 in the anal specimen but negative for this type in the vaginal specimen may derive benefit if her partner receives Gardasil, even if he is HPV-6 positive in the penile sample. The assumption is that protection via vaccination is pan-mucosal, via transudation of neutralizing antibodies; this protection may mediate transmission.
At months 2, 4, 6, 9 and 12.
Ziad El-Khatib, PhD
Canada: Health Canada